SIV disrupts the spatial organization of granuloma function during SIV-Mtb coinfection 4082

Abstract Description Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a leading infectious cause of death. The most important risk factor is co-infection with HIV. 70% of people living with HIV are on antiretroviral therapy (ART) but remain at higher TB risk. The hallmark of TB is a granuloma, a collection of immune cells with a lymphocyte ring around a macrophage region with central necrosis. HIV disruption of the immune responses against Mtb in granulomas remains poorly understood. We used a non-human primate (NHP) model of simian immunodeficiency virus (SIV) and Mtb co-infection, comparing granulomas from NHPs infected with Mtb, SIV/Mtb, or SIV/ART/Mtb. Cell dynamics were assessed in the inner and outer regions using spatial transcriptomics. Within each treatment group, differential gene expression was observed in macrophages from the inner versus the outer rings, which may affect how these macrophages interact with lymphocytes. Gene expression in Mtb granulomas was more spatially differentiated, with the inner core dominated by expression of metabolic pathways. SIV/Mtb granulomas were more inflammatory overall, and had fewer differential pathways between inner and outer regions, with the inner core especially enriched in inflammatory pathways. SIV/ART/Mtb granulomas had an intermediate phenotype, skewing closer to the Mtb NHPs. Understanding how HIV alters dynamics within granulomas to drive increased TB disease will be critical for vaccine and therapeutics development. Funding Sources Supported by NIH T32GM008208 (JM), NIH F31AI181616 (JM), NIH RO1 AI34195 (PLL, ZA), OTIS (PLL) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)